Ear infections, especially fungal ear infections, are common ear disorders, often occurring in warm and humid climates. Fungal otitis externa is a fungal infection of the external auditory canal and associated complications. It has been reported that as high as 30.4% of otitis externa patients exhibit symptoms of fungal otitis or inflammatory conditions of the ear.
Common symptoms of ear fungal infection include otalgia, otorrhea, hearing loss, aural fullness, pruritus and tinnitus. Several factors that may cause or enhance the rate of fungal infection include humid climate, the presence of cerumen (ear wax) acting as a support for fungal growth, configuration of the ear canal, weak immune function, diabetes, increased use of ototopical antibiotics, prolonged use of broad-spectrum antibiotics, use of systemic steroids, pregnancy, hearing aids with occlusive molds, trauma, and bacterial infections.
Common fungi that cause otitis externa are Aspergillus niger and Candida albicans, and treatment thereof can be tailored against these fungi. Other fungi may also cause otitis externa, and can also be treated by respective therapeutic agents. It is debatable whether identification of the causal agent is necessary for determining the appropriate treatment. One school of thought believes that the treatment should be based on the susceptibility of the identified species, whereas others believe that the treatment should based on efficacy and characteristics of the drug regardless of the causing microbes. An experienced Ear, Nose and Throat physician (ENT) can now routinely treat fungus without cultures, mostly by identifying the characteristic fungal elements on exam, and apply topical acidifying agents or specific antifungals. Thus, practitioners can identify the organism, or just treat the likely organisms empirically according to best practices, as desired.
Currently, there are four main classes of drugs for the treatment of fungal infections, including polyenes, azoles, nucleoside analogs and enchinocandins. The mechanism of action of the polyene and azole families involves an essential chemical component called ergosterol found in the fungal cell membrane. The drug binds to ergosterol and creates a polar pore in the fungal membranes, which results in the leaking of ions and other molecules from within the cell, which in turn kills the cell. The nucleoside analogs interfere with nucleotide synthesis, which prevents proper energy production, metabolism and signaling of the cell. Echinocandins are a novel class of antifungal agents, acting by interfering with cell wall biosynthesis. However, echinocandins are known to be embryotoxic, and dose adjustment is required for patients having liver diseases.
To date, most reported treatment involves a solution, cream, powder or ointment to be topically applied multiple times for a period of time from one week to one month. See, e.g. Table 2 of Munguia et al., “Ototopical antifungals and otomycosis: A review”, Int'l J. of Pediatric Otorhinolaryngology (2008) 72, 453-459. The prolonged treatment regimen causes inconvenience to the patients because either they have to visit a primary care physician or otolaryngologist multiple times, or for self-administered drugs, patients often forget to apply the drugs according to instruction, resulting in secondary proliferation of fungus and bacteria that may further extend the treatment period.
In addition, many drugs do not have complete efficacy for infection caused by multiple agents, and this can again prolong treatment times. Moreover, pure liquid form of drugs, such as ear drops, are less effective for treating chronic otitis externa especially because the liquids egress from the ear canal very rapidly; and, not all infected areas within the ear canal can be reached by the liquid because of gravity, especially in the upper half of the ear canal. Creams and ointments, in contrast, often remain in the ear and then have to be removed by the ENT.
U.S. Pat. No. 7,220,431 discloses a method for administering a pharmacological agent to the middle ear of a mammal by applying a formulation to the tympanic membrane of the mammal. The method does not teach how to treat an infection occurring at the auditory canal, such as otitis externa. The formulation is characterized by having a viscosity of less than 100,000 cps, and the formulation forms a gel after application to the tympanic membrane. However, the practical application of this patent may be problematic because once the ear canal is occluded, additional ear drops cannot be introduced. In addition, the solidified gel can be hard to remove by the patients after the infection symptoms are resolved. If the solidified gel remains too long within the ear canal after releasing all the active ingredients, recurrence of fungal and bacterial infection is likely.
U.S. Pat. No. 8,030,297 discloses a method for treating otic disorders selected from Meniere's disease, autoimmune ear disease, otitis media, acoustic trauma induced sensorineural hearing loss, drug-induced sensorineural hearing loss, sensorineural hearing loss, idiopathic sensorineural hearing loss, vertigo, and tinnitus. The method requires intratympanic administration of a pharmaceutical composition comprising a thermoreversible aqueous gel having 16% to 21% by weight of polyoxypropylene and polyoxyethylene and from 1 mg/ml to 70 mg/ml of a multiparticulate anti-inflammatory corticosteroid. The “intratympanic” administration and the targeted disorders make it clear that this patent does not treat otitis externa. Also, the patent does not teach the use of any antifungal agent for treating fungal infection.
There are also a couple of veterinary products available for animal use. POSATEX OTIC SUSPENSION™ by Intervet®/Schering-Plough Animal Health® contains Orbifloxacin, Mometasone Furoate Monohydrate and Posaconazole in a suspension. However, it has limited efficacy (against Pseudomonas aeruginosa and the yeast Malassezia pachydermatis) and the orbofloxacin is only approved for use in dogs. Further, it is required to be used daily for 7 consecutive days.
TRI-OTIC™ by Med-Pharmex® contains Gentamicin Sulfate, Betamethasone Valerate, and Clotrimazole. However, this formula also requires twice daily application into the ear canal for 7 consecutive days. Further, gentamicin is ototoxic and has limited efficacy (against Malassezia pachydermatis, formerly Pityrosporumcanis, and/or bacteria susceptible to gentamicin).
There are also a few combinations approved for use in humans, but all are of very limited efficacy. CIPRODEX® by Alcon® is 0.3% ciprofloxacin and 0.1% dexamethasone in a suspension. However, it has no efficacy against fungus, and is directed for twice daily use for seven days. CIPRO HC® a similar formulation containing ciprofloxacin and hydrocortisone and has the same limitations. Also CIPRO HC® is not sterilized and cannot meet the FDA mandate for sterilized otic medications. CORTISPORIN, available generically, contains neomycin and polymyxin B sulfates and hydrocortisone otic solution, but has the same limitations, and requires 3-4 applications a day for up to 10 days. Neomycin is also known for its ototoxicity.
Therefore, there is still a need for a medical formulation and method for treating fungal ear infections, such as otomycosis and otitis externa, that requires only a single administration and yet is still capable of eradicating a spectrum of fungal and bacterial infections and the coincident inflammation. There is a particular need for a formulation that is capable of maintaining the active agents within the ear canal of a patient such that only a single dose of the formulation is required to achieve a high cure rate of otomycosis and otitis externa.
Additionally, it has been documented that tympanic membrane perforations can be observed in fungal otitis externa. See Song et al., “Fungal otitis externa as a cause of tympanic membrane perforation: a case series.” Ear Nose Throat J., 2014 August; 93(8):332-6. FDA mandates all otic medications to be sterilized for this reason, and therefore there is the need for a long-lasting, single-dose and sterilized treatment high efficacy.
Furthermore, some of the above discussed Active Pharmaceutical Ingredients (API) have not been proven stable to heat or irradiate, and thus there are no commercial products with these API's that are sterile. Therefore, it would be beneficial if a formulation could be developed that was stable to sterilization methods.